Discovery and Development of Simeprevir (TMC435), a HCV NS3/4A Protease Inhibitor
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- 作者：脜sa Rosenquist ; Bertil Samuelsson ; Per-Ola Johansson ; Maxwell D. Cummings ; Oliver Lenz ; Pierre Raboisson ; Kenny Simmen ; Sandrine Vendeville ; Herman de Kock ; Magnus Nilsson ; Andras Horvath ; Ronald Kalmeijer ; Guy de la Rosa ; Maria Beumont-Mauviel
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：March 13, 2014
- 年：2014
- 卷：57
- 期：5
- 页码：1673-1693
- 全文大小：951K
- 年卷期：v.57,no.5(March 13, 2014)
- ISSN：1520-4804
文摘
Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors. However, new therapies are needed to improve cure rates, shorten treatment duration, and improve tolerability. Here we summarize the extensive medicinal chemistry effort to develop novel P2 cyclopentane macrocyclic inhibitors guided by HCV NS3 protease assays, the cellular replicon system, structure-based design, and a panel of DMPK assays. The selection of compound 29 (simeprevir, TMC435) as clinical candidate was based on its excellent biological, PK, and safety pharmacology profile. Compound 29 has recently been approved for treatment of chronic HCV infection in combination with pegylated interferon-伪 and ribavirin in Japan, Canada, and USA.